Pyrazole and pyrazolone aminoketones

ABSTRACT

COMPOUNDS OF THE FORMULA   (R7,R8-PHENYL)-CH(-OH)-CH(-R6)-NH-CH2-CH(-R5)-Y-X(-R1)   (-R2)(-R3)-R4   THEIR SALTS AND QUATERNARY AMMONIUM COMPOUNDS, AS WELL AS THEIR OPTICALLY ACTIVE ISOMERS OR DIASTEREOMERS WHERIN R1 TO R4 REPRESENT HYDROGEN, HALOGEN, LOWER ALKYL, ARALKYL, PHENYL, HYDROXYL, LOWER ALKOXY, NITRO OR LOWER CARBOALKOXY, R5 AND R6 ARE HYDROGEN OR METHYL, R7 AND R8 ARE HYDROGEN, HALOGEN OR LOWER ALKOXY, X IS A HETEROCYCLIC RING SYSTEM, MONO- OR CONDENSED BICYCLIC, WITH 1-4 HETERO ATOMS, IN WHICH THE INDIVIDUAL RINGS HAVE 5 TO 6 MEMBERS AND CAN ALSO CONTAIN 1 OR MORE CARBONYL GROUPS, Y IS -CO- OR -CH(OH)-. THESE COMPOUNDS HAVE PHARMACOLOGICAL ACTIVITY IN THAT THEY INCREASE THE CORONARY BLOOD FLOW BY SIMULTANEOUSLY CAUSING DILATION OF THE CORONARIES AND AN INCREASE IN CONTRACTION STRENGTH. THE PYRAZOLES AND PYRAZOLONES HAVE ANTIPHLOGISTIC ACTION.

United States Patent U.S. Cl. 260-310 R 17 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula their salts and quaternary ammonium compounds, as well as their optically active isomers or diastereomers wherein R to R represent hydrogen, halogen, lower alkyl, aralkyl, phenyl, hydroxyl, lower alkoxy, nitro or lower carboalkoxy, R and R are hydrogen or methyl, R and R are hydrogen, halogen or lower alkoxy, X is a heterocyclic ring system, monoor condensed bicyclic, with 1-4 hetero atoms, in which the individual rings have 5 to 6 members and can also contain 1 or more carbonyl groups, Y is CO- or CH(OH). These compounds have pharmacological activity in that they increase the coronary blood fiow by simultaneously causing dilation of the coronaries and an increase in contraction strength. The pyrazoles and pyrazolones have antiphlogistic action.

This application is a oontinuation-in-part of application Ser. No. 693,138, filed Dec. 26, 1967 and now Patent 3,514,465, May 26, 1970.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS The following heterocyclic ring systems, for example, come into consideration for the compounds according to the invention: furane, thiophene, pyrrole, pyrazole, thiazole, pyridine, pyrimidine, triazine, pyrazolone, benzofurane, benzothiophene, indole, quinoline, isoquinoline, benzodioxol, benzodioxane, decahydroisoquinoline, benzothiazole and benzimidazole.

The compounds according to the invention of the above Formula I can be produced in a known manner by (a) Reacting a compound of the formula \}|{-C O-CH2 RB/ILA 1'15 11 with a compound of the formula R7 HzN-CH(OH)-C in RB III in the presence of formaldehyde or a formaldehyde source and a solvent.

(b) Reacting a compound of the formula Ra 34 r IV Patented Aug. 22, 1972 or the corresponding Mannich base of the formula (c) Reacting a compound of the formula R2 R1 l X-Y-CHCH:W s 4 a with a compound of the formula in which W and V are different and are either halogen or NH in the presence of a basic substance and, if desired, in the event Y is CO, reducing such group to a CH(OH) group and, if desired, coverting the bases produced into their pharmacologically acceptable acid addition salts or quaternary ammonium salts.

The process according to method (a) is carried out in the usual manner at a temperature between 20 and 150 C. Alcohols, dioxane, glacial acetic acid and the like come into consideration as solvents.

The process according to method (b) in general when using an unsaturated ketone of Formula IV can be carried out at temperatures between 20 and C. in an inert solvent, such as, ether, acetone, dioxane or chloroform, whereas when the corresponding Mannich base is used, which during the reaction is transformed into an intermediate of Formula IV, the reaction temperature used is normally higher, preferably, between 80 and C., and solvents such as water, alcohol/ water, or a two phase sys tem such as benzene/water toluene/water come into consideration.

The process according to method (0) is usually carried out at elevated temperatures in a solvent such as alcohols, ether, dimethyl formamide and the like.

The compounds produced which contain optically active carbon atoms and which as a rule are produced as racemates can be resolved into their optically active isomers in the usual manner, for example, with the aid of an optically active acid. It, however, is also possible to employ optically active compounds or diastereomers as the starting materials whereby the end product in the corresponding pure optically active form of diastereomeric configuration is obtained.

The free bases cas be converted into their salts with the usual pharmacologically acceptable acids such as HCl, HBr, H 80 acetic acid, citric acid, succinic acid, maleic acid, fumaric acid, lactic acid, p-toluene sulfonic acid and the like. Those compounds containing basic tertiary nitrogen atoms can be converted to their quaternary salts with the usual pharmacologically acceptable quaternizing agents such as the lower alkyl halides. The free bases can be removed from the salts, for example, by treatment with aqueous NaOH and other salts can be prepared from such free bases.

As already indicated, the compounds according to the invention have a pharmacological activity in that they increase the coronary blood flow by causing dilation of the coronaries, as well as an increase in contraction strength of the heart.

When tested on the isolated guinea pig heart according to Langendorlf (Pfliigers Arch. 61, 291, 1895) it was found that the compounds according to the invention were active in doses between 10-500 pig/heart (,ug.-'y-miCIO The novel compounds can be used, if desired, also in combination with other medicaments in the form of pharmaceutical compositions suited for enteral, parenteral, oral or per lingual application.

The acute toxicity of the compounds according to the invention when tested on mice by the method of Miller and Tainter (Proc. Soc. exper. Biol. a Med. 57, 261, 1944) expressed as the LD 50 is between 100 mg./kg. and 5000 mg./kg. oral.

The individual doses for human beings, depending on form of administration are between 0.5 and 100 mg., once or more times a day.

The following examples will serve to illustrate the compounds according to the invention. For sake of simplicity the symbol Z is used in the structural formulae and nomenclature of a number of the examples to represent, respectively CH3 and 2- [3-pheny1-3-hydroxy-propyl-(2 -amino] -ethyl Example 1.1 {2-[3-phenyl-3-hydroxy-propyl-(2)- amino ethyl}-thienyl-(2)-ketone, that is, 1-{Z}-thienyl- Method (a).l2.6 g. (0.1 mol) of 2-acetyl-thiophene. 18.7 g. (0.1 mol) of l-norephedrine-HCl and 4 g. (0.13 mol) of paraformaldehyde were dissolved in 20 ml. of isopropanol and after addition of 0.2 mol of concentrated HCl boiled under reflux for 2 hours. hereafter 100 ml. of acetone were added to the still warm solution. The hydrochloiide which crystallized out upon cooling was purified by recrystallization from ethanol. Its melting point was 191-192 C. and the yield 17 g.

Method (b).l.5 g. (0.01 mol) of l-norephedrine were dissolved in 50 ml. of ether and 2.7 g. (0.02 mol) of thienyl vinyl ketone dissolved in 10 m1. of ether added thereto. After /2 hour 2 g. of the base separated out which after recrystallization from ethanol had a melting H point of 118l20 C. The hydrochloride produced therefrom had a melting point of 19l-192 C.

Method (c).5.2 g. (0.03 mol) of 2-[B-chloropropionyl1-thiophene were dissolved in dimethyl formamide and united with a solution of 4.5 g. (0.03 mol) of lnorephedrine and 4 g. (0.03 mol) of triethylamine in 25 ml. of dimethyl formamide. After 1 hour the triethylamine HCl which was formed was filtered off and the filtrate acidified with isopropanolic HCl. Subsequently, the HCl salt was precipitated from the solution by addition of ether and recrystallized from ethanol. Its melting point was 19 l 192 C. and the yield was 7 g.

Example 2.1-{Z}-phenyl-(2)-ltetone 11 g. (0.1 mol) of 2-acetyl-furan, 18.7 g. (0.1 mol) of l-norephedrine-HCl and 4 g. (0.13 mol) of paraform- Ill aldehyde were heated for 2 hours under reflux in 20 ml. of isopropanol with the addition of drops of ethanolic HCl. The HCl salt which had precipitated out was stirred up with 50 ml. of acetone and filtered off. It was purified by recrystallization from ethanol. Its melting point was 186187 C. and the yield was 10.5 g.

Example 3 .1-{Z}- [4-methyl-thiazolyl-( 2) -ketone 7 g. (0.05 mol) of 4-methyl-2-acetyl-thiazole, 9.4 g. (0.05 mol) of l-norephedrine-HCI, 2 g. (0.067 mol) of paraformaldehyde and 5 drops of isopropanolic HCl in ml. of isopropanol were reacted and processed as in Example 2. The HCl salt was recrystallized from methanol. Its melting point was 197-199" C. and the yield 7 g.

11.5 g. of 4-acetyl-antipyrin (0.05 mol), 9.5 g. of 1- nOrephedrine'HCl (0.05 mol) and 2 g. of paraforrnaldehyde (0.067 mol) were introduced into 20 ml. of isopropanol and 5 drops of isopropanolic HCl added thereto and the mixture boiled for a total of 5 hours during which after 3 hours an additional 1 g. of paraformaldehyde was added. Thereafter the solvent was distilled off and the residue treated with aqueous soda. The oily Mannich base produced was crystallized with the aid of ether. It formed the dihydrochloride with 2 mol of HCl which was recrystallized from ethanol. Its melting point Was 206208 C. and the yield was 9 g.

Example 5.-1-{Z}-pyridyl-(3 -ketone COZ 40 g. (0.33 mol) of 3-acetyl-pyridine, 18.7 g. (0.1 mol) of 1-n0rephedrine-HCl and 3 g. (0.1 mol) of paraformaldehyde were boiled under reflux in 15 ml. of isopropanol for a total of 3 hours. An additional 1 g. of paraformaldehyde was added after 1 hour. Thereafter the reaction mixture was diluted with acetone and the precipitated HCl salt was recrystallized from methanol/ethanol (1:2). Its melting point was 187189 C. and the yield 7 g.

Example 6.1-{Z}-[2,4-dimethyl-thiazolyl-(5 -ketone NCII; l l...

g. (0.16 mol) of 2,4-dimethyl-S-acetyl-thiazole, g. (0.16 mol) of l-norephedrine-HCI and 5 g. (0.16 mol) of paraformaldehyde were introduced into ml. of isopropanol and 15 drops of isopropanolic HCl added thereto. The mixture was boiled on a water bath for a total of 1 hour. An additional 1.5 g. of paraformaldehyde was added after /2 hour. The reaction solution was diluted with 100 ml. of acetone while still warm. The HCl salt which precipitated out was recrystallized from ethanol. Its melting point was 208-210 C. and the yield 6.6 g.

(5)]-ketone 5 g. (0.035 mol) of 4-methyl-2hydroxy-S-acetylthiazole, 6.6 g. (0.035 mol) of 1-norephedrine-HC1 and 1.5 g. (0.05 mol) of paraformaldehyde were boiled under reflux for 2 hours in 20 ml. of glacial acetic acid. The HCl salt which crystallized out on cooling was recrystallized from methanol/ethanol (1 1). Its melting point was 209210' C. and the yield 4.5 g.

Example 8.-1-{Z}-cumaronyl-ketone 40 g. (0.25 mol) of Z-acetyl cumarone, 46.5 g. (0.25 mol) of 1-norephedrine-HCl and 7.5 g. (0.25 mol) of paraformaldehyde were dissolved in 200 ml. of isoamyl alcohol and after addition of 10 drops of ethanolic-HCl boiled under reflux for /2 hour. Then an additional 2.5 g. (0.083 mol) of paraformaldehyde were added and the mixture refluxed for a further hour. The solution was diluted with 100 ml. of acetone while still warm. Upon cooling the I-ICl salt crystallized out. It was recrystallized from ethanol. Its melting point was 199-200 C. and the yield 31.5 g.

Example 9.-1-3-{3-[3-pl1enyl-3-hydroxy-propyl- (2)-amino]-propionyl}-thionaphthene 17.6 g. (0.1 mol) of 3-acetyl-thionaphthene, 18.7 g. (0.1 mol) of l-norephedrine-"HCI and 4.5 g. (0.15 mol) of paraformaldehyde were boiled under reflux for 2 hours in 50 ml. of isopropanol. The solution was then diluted with 100 ml. of acetone while still warm. Upon cooling the HCl salt precipitated out. It was recrystallized from methanol. Its melting point was 220-221 C. and the yield 18.5 g.

Example 10.1-3-{3-[3-phenyl-3-hydroxy-propyl- (2) -amino] -propionyl}- 1-methyl-ind0le 25 g. (0.13 mol) of l-methyl-3-acetyl-indole, 24.3 g. (0.13 mol) of l-norephedrine-HCI and 5 g. (0.17 mol) of paraformaldehyde were dissolved in 100 ml. of isopropanol and boiled under reflux for a total of 6 hours. After the second and fourth hours an additional 2.5 g. of paraformaldehyde were added. Thereafter the solvent was distilled off and the residue dissolved in warm acetone. The lHCl salt which crystallized out on cooling was recrystallized from ethanol. Its melting point was 194- 195 C. and the yield 22 g.

Example 1 1.1-5-{3-[3-phenyl-3-hydroxy-propyl- (2) -amino] -propionyl}-henzodioxol-( 1,3

8 g. (0.048 mol) of 5-acetyl-benzodioxol-(1,3), 9.1 g. (0.048 mol) of l-norephedrine-HCI and 2.9 g. (0.097 mol) of paraformaldehyde were boiled on a water bath for 2 hours in 30 ml. of isopropanol after addition of 5 drops of isopropanolic HCl. After addition of 100 ml. of acetone to the warm reaction solution, the HCl salt precipitated out. It was recrystallized from ethanol. Its melting point was 195-197 C. and the yield 9 g.

Example 12.-1-4-{3-[3-phenyl 3 hydroxy-propyl-(2)- amino]-propionyl}-1,3-dimethy1 and -1,5-dimethyl pyrazole (mixture) 26 g. (0.19 mol) of the isomeric mixture of 1,3- and 1,5-dimethyl-4-acetyl-pyrazole formed during the synthesis, 37.4 g. (0.2 mol) of l-norephedrine-HCl and 9 g. (0.3 mol) of paraformaldehyde were boiled under reflux under an atmosphere of nitrogen in 150 ml. of isopropanol for 3 hours. Upon cooling the HCl salt crystallized. It was recrystallized from isopropanol and then twice from ethanol. Its melting point was 196 C. and the yield 11 g.

Example 13 .--l -{Z}-quinolyl- 3 -ketone 10 g. (0.058 mol) of 3-acetyl quinoline, 11.2 g. (0.058 mol) of l-norephedriue-HCl and 1.6 g. (0.058 mol) of paraformaldehyde were boiled under reflux on a Water bath in 75 ml. of isopropanol for 2.5 hours. An additional 0.8 g. (0.026 mol) of paraformaldehyde was added after 1 hours boiling. Upon addition of 150 ml. of acetone the HCl salt precipitated out. It was recrystallized from methanol. Its melting point was 205-206 C. and the yield 5 g.

Example 14.-1-{Z}-is0quinolyl-(4)-ketone 5 g. (0.024 mol) of 4-acetyl isoquinoline-HCI, 4.6 g. (0.024 mol) of l-norephedrine-HCI and 0.7 g. (0.024 mol) of paraformaldehyde were boiled on a water bath for 2.5 hours in 50 ml. of a 1:1 mixture of ethanol-isopropanol and an additional 0.4 g. (0.012 mol) of paraformaldehyde was added after 1 hours boiling. Upon cooling, the dihydrochloride salt precipitated out. It was recrystallized from ethanol. Its melting point was 208 C. and the yield 3 g.

Example l5.1-{Z}- l,2,4-trimethyl-5-carbethoxypyrrolyl- (3 ]-ketone 1.7 g. (0.066 mol) of 6-acetyl-1,4-benzodioxane, 12.5 g. (0.066 mol) of l-norephedrine-HCI and 2 g.

(0.067 mol) of paraformaldehyde were boiled on a Water bath in 33 ml. of isopropanol for 2 hours. An additional 2 g. (0.067 mol) of paraformaldehyde were added after 1 hours boiling. The solvent was distilled E and the residue treated with acetone. The HCl salt which precipitated out was recrystallized from ethanol. Its melting point was 201 C. and the yield 7.5 g.

Example 17.--1-2-{3-[3-phenyl-3-hydroxy-propyl-(2) amino] -propionyl}-benzodioxane-( 1,4)

11 g. (0.061 mol) of 2-acetyl-l,4-benzodioxane, 11.6 g. (0.062 mol) of l-norephedrine-HCI and 1.85 g. (0.062 mol) of paraformaldehyde were reacted in 30 ml. of isopropanol and processed as in Example 16. The melting point of the HCl salt was 178 C., and the yield 8 g.

Example 18.1-{Z}-[2-benzyl-10-hydroxy-decahydroisoquinolyl- (4) ]-ketone 11 g. (0.0339 mol) of 2-benzyl-4-acetyl-10-hydroxydecahydroisoquinoline-HC1, 6.5 g. (0.035 mol) of 1- norephedrine-HCl and 1.4 g. (0.047 mol) of paraformaldehyde were boiled on a water bath for 2 hours in 35 ml. of isopropanol. An additional 1.4 g. of paraformaldehyde were added after 1 hours boiling. The solvent was then distilled 011 and acetone and ethyl acetate added to the residue. The dihydrochloride produced was recrystallized from ethanol. Its melting point was 182- 183 C., and the yield 7 g.

Example 19.--1-{Z}- [-nitro-fury1- (2) ]-ketone 11.6 g. (0.075 mol) of 2-acetyl-5-nitro-furane, 14 g. (0.075 mol) of l-norephedrine-HCI and 3 g. (0.1 mol) of paraformaldehyde in 50 m1. of isopropanol were heated on a water bath for 3 hours. The I-ICl salt which precipitated out upon cooling was recrystallized from 80% ethanol. Its melting point was 210 C., and the yield 3 g.

Example 20.1-4-{3-[3-phenyl-3-hydroxy-propyl-(2)- amino]-propionyl}-1,3,5-trimethyl pyrazole CH CO-Z 1 N HCH:

27 g. (0.178 mol) of 1,3,S-trimethyl-4-acetyl-pyrazole, 33 g. (0.177 mole) of l-norephedrine-HCl and 10.8 g. (0.36 mol) of paraformaldehyde in 150 ml. of isopropanol were heated for 2 hours on a water bath. Thereafter the solvent was distilled off and 100 ml. acetone were added to the residue. The HCl salt which precipitated was recrystallized from isopropanol. Its melting point was 191 C. and the yield was 14.5 g.

Example 21.-1-4-{3-[3-phenyl-3 hydroxy-pr0pyl-(2)- amino]'propionyl}-1-benzyl-3,S-dimethyl-pyrazole CH: CO-Z 1 [0H,

13.5 g. (0.0624 mol) of 3,S-dimethyl-1-benzyl-4-acetylm J-CO-CHz-CHr-NH-4hH-CH@EQ 28 g. (0.119 mol) of d,l-3-(3-fluoro-4-methoxy-phenyl)-3-hydroxy-propyl-(2)-amine-HCl, 15 g. (0.119 mol) of 2-acetyl-thiophene and 7.2 g. (0.24 mol) of paraformaldehyde were reacted in 200 ml. of isopropanol and processed as in Example 21. The RC] salt was recrystallized from ethanol. Its melting point was 208 C. and the yield was 10 g.

Example 23.-1-{1-[3-phenyl-3-hydroxy-propyl-(2)- amino]-propyl-(2)}-thienyl-(2)-ketone 43 g. (0.307 mol) of 2-propionyl-thiophene, 57.7 g. (0.308 mol) of l-norephedrine-HCI and 18.4 g. (0.614 mol) of paraformaldehyde were heated on a water bath in 50 ml. of isopropanol for 1 hour. ml. of acetone were added to the reaction solution and the HCl salt which precipitated out recrystallized from ethanol. Its melting point was 208 C. and the yield was 16.5 g.

Example 24.-1-{Z}-5-chloro-thienyl-(2)-ketone 30 g. (0.187 mol) of 2-acetyl-5-chloro-thiophene, 35 g. (0.187 mol) of l-norephedrine-HCI and 5.6 g. (0.187 mol) of paraformaldehyde were heated in 50 ml. of isopropanol and processed as in Example 21. The HCl salt was recrystallized from ethanol. Its melting point was 198 C. and the yield was 16 g.

Example 25.d,l-{2-[2-(2-chloro-phenyl)-2-hydroxyethylamino]-ethyl}-thienyl-(2)-ketone 12.6 g. (0.1 mol) of Z-acetyl-thiophene, 20.8 g. (0.1 mol) of d,l-2-(2-chl0ro-phenyl)-2-hydr0Xy-ethyl-amine- HCl and 4.5 g. (0.15 mol) of paraformaldehyde were heated on a water bath for 2 hours in 100 ml. of isopropanol. Thereafter the solvent was distilled off and the residue caused to crystallize by addition of ethyl acetate. The HCl salt produced was recrystallized from ethanol. Its melting point was 15 8-160 C. and the yield was 4 g.

Example 26. [3-phenyl-3-hydroxy-propyl-(2)]-{3- [4- phenyl-thiazolyl-(2)]-3-hydroxy-propyl-(1)}-amine 6 g. (0.015 mol) of 1-{Z}-[4-phenyl-thiazolyl-(2)]- ketone-HCI were suspended in 60 ml. of methanol and reduced by the addition of 0.6 g. (0.016 mol) of sodium borohydride. After 1 hour the solvent was distilled off and the residue dissolved in acetone. Fumaric acid was added to such solution to precipitate out the fumarate salt. The base was again set free from the fumarate with aqueous NaOH. The resulting oily base was taken up in ether and converted to the HCl salt with isopropanolic HCl and such salt recrystallized from ethanol. Its melting point was 1781'81 C. and the yield was 2.5 g.

Example 27.- 3-phenyl-3-hydroxyapropyl-(2)]-{3- [thienyl-(2)]-3-hydroxy-propyl-(l)}-'amine 63 g. (0.2 mol) of l-{Z}-thienyl(2)-ketone-HCl and 300 g. of aluminum isopropylate were heated to 130 C. for 2 hours in 2 liters of isopropanol and the acetone produced during the reduction distilled oii over a column. After 7 hours the cooled solution was decomposed by addition of 100 g. of citric acid in 200 ml. of water and then rendered strongly alkaline with aqueous NaOH. The organic phase was dried over calcium oxide and the solvent distilled off under vacuum. The amino alcohol product melted at l23l25 C. after it was recrystallized from 50% ethanol. Upon addition of an equimolar quantity of HCl a HCl salt was obtained which had a melting point of 152-155 C. The yield was 13 g.

Example 28.-[3-phenyl-3-hydroxy-propyl-(2) ]-{3- [cumaronyl- 2) ]-3-hydroxy-propyl-( 1 )}-amine 18 g. (0.0 5 mol) of l-{Z}-cumaronyl-ketone-HCl were suspended in 100 ml. of ethanol and reduced at room temperature with 2 g. of sodium borohydride dissolved in 50 ml. of ethanol. After 1 hour, 50 ml. of concentrated HCl were added and the NaCl produced filtered off. The solvent was then distilled off under vacuum and the residue recrystallized from isopropanol/ethyl acetate (1:1). The HCl salt produced melted at 210-215 C. with decomposition. The yield was 11 g.

Example 29.--[3-phenyl-3-hydroxy-propy1- 2) [3- thionaphthenyl-( 3) ]-3-hydroxy-propyl-( l ]}-amine 19 g. (0.05 mol) l-3-[phenyl-3-hydroxy-propy1-(2)- amino]-propionyl}-thionaphthene-HCl were suspended in 100 ml. of ethanol and reduced with 2 g. of sodium borohydride in 50 ml. of ethanol at room temperature. After 1 hour the reaction mixture was filtered and the solvent distilled off and the residue dissolved in ether. The HCl salt was precipitated from the ether solution by addition of ethanolic HCl and recrystallized from isopropanol. Its melting point was 167-170 C. and the yield was 12 g.

Example 30.-l-4- [3-[3-phenyl-3 -hydroxypropyl-(2)- amino] -propionyl]-1-phenyl-5-methyl pyrazole C O-CHz-CHz-NH-C H C Ha 45 g. (0.0225 mol) of 4-acetyl-5-methyl-l-phenylpyrazole, 0.75 g. of paraformaldehyde and 4.5 g. (0.0248 mol) of l-norephredrin-HCI in 40 ml. of isopropanol were heated under reflux for 2 hours. After the first hour an additional 0.75 g. of paraformaldehyde were added. The HCl salt that precipitated from the reaction solution was recrystallized from ethanol. Its melting point Was 221 C. and the yield was 2.5 g.

The pyrazole and pyrazolone compounds of the present invention in addition to the pharmacological activities noted earlier have an inflammation repressing activity.

The antiphlogistic action of the pyrazoles and pyrazolones was tested on the carrageenin edema of the rats paw using the method of Domenjoz et al. (Arch. exp. Pharm. Path 230 (1957) 325).

In these tests, when the compounds were applied orally at dosages in the range of 1 to 500 mg/kg. of body weight strong antiphlogistic activity was noted. The best of the compounds had an edema repression of 50% at an oral dosage of 3 to 10 mg./kg.

To estimate the activity, the known antiphlogistic compound salicylamide was used as a standard. Lower dosages were required with most of the compounds of the invention to get an activity equal to that of salicylamide.

The indications for the compounds of the invention as inflammation repressing medicines are chronic polyarthritis rheumatic illnesses post traumatic infiammations swellings at fractures thrombophlebitis in any form (including post operative) bursitis synovitis collagenoses (polymyositis, periartiitis) gout The pharrnocological handling of the compounds is according to the customary standard procedures, if desired in combination with other pharmaceutically active materials. The application, for example, can be enteral, parenteral, oral or per lingual as set forth above. The individual dose according to the indicated field and type of dispensing can be between 0.1 and 500 mg, one or more times a day.

What is claimed is:

l. A compound selected from the group consisting of where n is 0 to 2, R is selected from the group consisting of hydrogen and lower alkyl, R and R are selected from the group consisting of hydrogen and methyl, R, and R are selected from the group consisting of hydrogen, halogen and lower alkoxy, m is selected from the group consisting of 0 and 1, R and R are selected from the group consisting of hydrogen, lower alkyl, benzyl and phenyl and Y is selected from the group consisting of CO- and -CH(OH).

2. A compound according to claim 1 having formula (a).

3. A compound according to claim 2 wherein R R and R are hydrogen, R is methyl and Y is -CO.

4. A compound according to claim 3 which is selected from the group consisting of 1-4[3-[3-phenyl-3-hydroxy- 1 1 propyl-(2)-amino]-propionyl]-'1,3-dimethyl pyrazole and l-4- [3 3-phenyl-3 hydroxypropyl- (2) amino] propionyl] 1,5-dimethyl pyrazole.

5. A compound according to claim 3 which is l-4-[3-[3- phenyl 3 hydroxypropyl-(Z)aminol]-propionyl]-1,3,5- trimethyl pyrazole.

6. A compound according to claim 3 which is l-4-[3-[3- phenyl 3 hydroxypropyl-(Z)amino]propionyH-l-benzyl-3,5-dimethyl pyrazole.

7. A compound according to claim 3 which is l-4-[3-[3- phenyl 3-hydroxypropyl-(2)amino]-propionyl]-1-phenyl-S-methyl pyrazole.

8. A compound according to claim 1 having formula (b).

9. A compound according to claim 8 having the formula (IMHa CHr-N o=o omomQ CHa-C=CCOCH2CH2NHCH a 10. A compound according to claim 1 which is selected from the group consisting of pyrazolone compounds of the formula:

wherein Z is l CHOH n is l or 2 and R is methyl, phenyl or benzyl.

11. A compound according to claim 1 wherein R and R are selected from the group consisting of hydrogen, methyl, benzyl or phenyl and R is hydrogen or methyl.

12. A compound according to claim 11 where Y is CO.

13. A compound according to claim 12 wherein R and R are hydrogen.

14. A compound according to claim 12 wherein R is hydrogen or methyl.

15. A compound according to claim 14 wherein R and R are hydrogen.

16. A compound according to claim 1 wherein R in formula (a) is hydrogen or lower alkyl, R in formula (b) is methyl in the 5 position and m is 1, R is hydrogen, Y is CO, R is a methyl group, R is hydrogen, halogen or lower alkoxy in the para position and R is hydrogen.

17. A compound according to claim 16 wherein any lower alkyl group present is methyl and R is hydrogen or halogen.

References Cited UNITED STATES PATENTS 3,478,032 11/1969 Arya 2603l0 R HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.R.

260-310 A, 347.8, 296 R, 326.5 R, 306.8 R, 289 R, 326.16, 256.4 R, 251 R, 304, 309.2, 340.3; 424273 

